RESPONSES OF NORMAL HUMAN KERATINOCYTES TO CYTOKINES

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I am currently working in the laboratory of Dr. Karl Munger attempting to characterize the nature of the responses of normal human keratinocytes to the cytokines TNF-alpha and TRAIL. Through their respective receptors, these cytokines can alternately cause growth arrest or apoptosis, depending upon conditions. Dr. Munger's lab studies the effects of the human papillomavirus on cell cycle control. This virus, whose natural host is the keratinocyte, attempts to take over control of the cell by expressing proteins which interfere with regulation of the natural cycle of cell growth and division. This permits the virus to use cellular machinery to replicate its own viral genome at the expense of the cell itself. These viral proteins also have the effect of altering an infected cell's responses to the protective cytokines produced by the body to defend against just such an infection. Among these cytokines are TNF-alpha and TRAIL. At this point in my research, I have discovered that human keratinocytes exhibit a dramatic growth arrest in response to small amounts of TNF-alpha and TRAIL alone and an apoptotic response when these compounds are combined with protein synthesis inhibitor cycloheximide. In the second phase of my research I will transfect papillomavirus oncoproteins into keratinocytes in an attempt to recognize changes in the growth arrest and apoptotic responses to TNF-alpha and TRAIL. I also will characterize changes in mRNA expression and stability of some of the proteins involved in cell cycle control.